Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/84—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
  • Y10S530/86—Renin inhibitors

Definitions

• the invention relates to compounds of the formula wherein R 1 by a thio, sulfinyl or sulfonyl group substituted acyl with the exception of an optionally N-substituted acyl residue of a natural amino acid, A an optionally N-alkylated a-amino acid residue, the N-terminal with R 1 and C-terminal with the group -NR 2 - is connected, R 2 is hydrogen or lower alkyl, R 3 is hydrogen, lower alkyl, optionally etherified or esterified hydroxy-lower alkyl, cycloalkylene, cycloalkyl-lower alkyl, bicycloalkyl-lower alkyl, tricycloalkyl-lower alkyl, aryl or aryl-lower alkyl, R 4 hydroxy, etherified or esterified hydroxy, R 5 optionally etherified or esterified hydroxy-lower alkyl, cycloalkyl, cycloal
• the C atoms substituted by R 3 , R 4 and R 5 can have the R, S or R, S configuration.
• Preferred compounds of the formula I are those in which the C atoms substituted by R 3 and R4 have the S configuration.
• Preferred substituents Ri are acyl groups of the formula wherein R a is unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, mono-, bi- or tricycloalkyl, cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, aryl-lower alkenyl, unsubstituted or substituted heteroaryl, heteroaryl-lower alkyl, unsubstituted or substituted-hydrogen or substituted-unsubstituted or substituted or substituted , Mono-, bi- or tricycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, m 0, 1 or 2, n 0, 1 or 2, p 0, 1 or 2 and q 0, 1, 2, 3 or 4 represents.
• the methine carbon atom in partial formula 1a and, if m is 1, also the sulfur atom can be in the R, S or R, S configuration.
• Lower alkyl R a preferably has 1-7 carbon atoms and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, which is etherified by one or more functional groups, for example hydroxyl, such as hydroxyl, for example lower alkoxy Methoxy or ethoxy, or phenyloxy, esterified hydroxy, for example lower alkanoyloxy, such as acetoxy, halogen, for example chlorine or bromine, hydroxysulfonyloxy, carboxy, esterified carboxy, for example lower alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, amidated carboxy, for example carbamoyl or mono- or di-lower alkylcarbamoyl, such as methyl or dimethyl carbamoyl, cyano, amino, substituted amino, for example mono-lower alkylamino, di-lower alky
• Substituted lower alkyl R a is, for example, hydroxy-lower alkyl, for example 2-hydroxyethyl, lower alkoxy-lower alkyl, for example lower alkoxy-ethyl, such as 2-methoxyethyl, phenoxy-lower alkyl, for example 2-phenoxyethyl, lower alkanoyloxy-lower alkyl, for example lower alkanoyloxyethyl, such as 2-acetoxyethyl, halo-lower alkyl, for example halogen Chloro or 2-bromoethyl, hydroxysulfonyloxy lower alkyl, for example 2-hydroxy sulfonyloxyäthyl, carboxy such as carboxymethyl or 2-carboxyethyl, Niederalkoxycarbonylniederalkyl, including lower alkoxycarbonylmethyl or Niederalkoxycarbonyläthyl, such as methoxycarbonylmethyl, 2-methoxycarbon
• Lower alkenyl R a contains, for example, 2-7, in particular 2-4, carbon atoms and is, for example, vinyl, allyl or 2- or 3-butenyl.
• Lower alkenyl R can be substituted by the same substituents as lower alkyl, for example by hydroxy, etherified hydroxy, for example methoxy, esterified hydroxy, for example acetoxy, halogen, for example chlorine or bromine, carboxy, esterified carboxy, for example methoxycarbonyl or ethoxycarbonyl, or amidated carboxy, for example Carbamoyl.
• Lower alkynyl R a contains, for example, 2-7, in particular 2-4, carbon atoms and is, for example, ethynyl, 1-propynyl or 2-propynyl.
• Cycloalkyl R a or R b contains, for example, 3 to 8, in particular 3 to 6, carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• B i c ycloalkyl R a or R contains, for example 5 - 10, especially 6 - 9, C atoms and is, for example, bicyclohexyl, heptyl, octyl, nonyl or decyl, including bicyclo [3.1.0] hex-l- , -2- or -3-yl, bicyclo [4.1.0] - hept-1- or -7-yl, bicyclo [2.2.1] hept-2-yl, for example endo- or exo-norbornyl, bicyclo [3.2.1] oct-2-yl, bicyclo [3.3.0] oct- 3-yl or bicyclo [3.3.1] non-9-yl, furthermore a- or ⁇ -decahydronaphthyl.
• Tricycloalkyl R a or R contains, for example, 8-10 carbon atoms and is, for example, tricyclo [5.2.1.0 2,6 ] dec-8-yl or adamantyl, such as 1-adamantyl.
• Cycloalkyl-lower alkyl R a contains, for example, 4-10, in particular 4-7, carbon atoms and is, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
• cycloaliphatic or cycloaliphatic-aliphatic radicals mentioned can be substituted by the same substituents as lower alkyl R a .
• Aryl R a or R b contains, for example, 6 to 14 carbon atoms and is, for example, phenyl, indenyl, for example 2- or 4-indenyl, 1- or 2-naphthyl, anthryl, for example 1- or 2-anthryl, phenanthryl, for example 9 -Phenanthryl, or acenaphthenyl, for example 1-acenaphthenyl.
• Aryl R or R b is, for example, lower alkyl, for example methyl, hydroxy, lower alkoxy, for example methoxy, acyloxy, for example lower alkanoyloxy such as acetoxy, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, acylamino, for example tert-butoxycarbonylamino, or halo, For example chlorine, bromine or iodine, substituted, where the substituent can be in any position of the aryl radical, for example in the o-, m- or p-position of the phenyl radical, and the aryl radical can also be substituted several times with the same or different substituents.
• Aryl-lower alkyl R a has, for example 7 to 15 carbon atoms and includes, for example, a said lower alkyl R a unsubstituted or substituted, optionally branched radical and b by aryl is R a or R-mentioned unsubstituted or substituted radical.
• Such aryl-lower alkyl is for example benzyl, lower alkyl benzyl, such as 4-methylbenzyl, lower alkoxybenzyl, such as 4-methoxybenzyl, 2-phenylethyl, 2- (p-hydroxyphenyl) ethyl, diphenylmethyl, di- (4-methoxyphenyl) methyl, trityl or a- or ß-naphthylmethyl.
• Arylniederalkenyl R a has, for example 8 to 16 carbon atoms and includes, for example an under lower alkenyl R a said unsubstituted or substituted radical and a referred aryl R a or R b unsubstituted or substituted radical.
• Such Arylniederalkenyl for example, styryl, 3-phenylallyl, 2- (a-naphthyl) vinyl or 2- ( ⁇ -naphthyl) vinyl.
• R a or R is mono-, bi- or tricyclic and contains one to two nitrogen atoms and / or an oxygen or sulfur atom.
• R a or R b is, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ⁇ -carbolinyl or a benzene-fused, cyclopenta-, cyclohexa- or cyclohe- annulated derivative of these residues.
• This heterocycle can be on a nitrogen atom by oxido, lower alkyl, for example methyl or ethyl, phenyl or phenyl-lower alkyl, for example benzyl, and / or on one or more carbon atoms by lower alkyl, for example methyl, phenyl, phenyl-lower alkyl, for example benzyl, halogen, for example chlorine, hydroxy, lower alkoxy, for example methoxy, phenyl-lower alkoxy, for example benzyloxy, or oxo substituted and partially saturated and is for example 2- or 3-pyrrolyl, phenyl-pyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2- Furyl, 2-thienyl, 4-imidazolyl, methyl-imidazolyl, e.g.
• Heteroaryl-R a includes, for example, a lower alkyl mentioned under R a unsubstituted or substituted radical and a heteroaryl under b R a or R-mentioned unsubstituted or substituted radical and is, for example 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylmethyl, 2 - (2-, 3- or 4-pyridyl) ethyl, 4-imidazolylmethyl, 2- (4-imidazolyl) ethyl, 2- or 3-indolylmethyl, 2- (3-indolyl) ethyl or 2-quinolylmethyl.
• Hydroxy R a is unsubstituted or substituted, for example, by lower alkyl or aryl and is, for example, hydroxy, methoxy, ethoxy n-butoxy, phenoxy, 4-hydroxyphenoxy or 3,4-methylenedioxyphenoxy.
• Amino R a is unsubstituted, substituted by one or two lower alkyl groups or by aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or arylmethoxycarbonyl or part of a five- or six-membered heterocycle containing one or two nitrogen atoms and, if desired, an oxygen or sulfur atom and is, for example, amino, methylamino, ethylamino, Isopropylamino, n-butylamino, dimethylamino, diethylamino, benzylamino, acetylamino, pivaloylamino, methoxy-, ethoxy- or tert-butoxycarbonylamino, benzyloxycarbonylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-methyl-4-pyridazinyl or 4-morpholinyl Thiomorpholinyl.
• A is a divalent residue of an a-amino acid, for example a natural a-amino acid with the L configuration, as normally found in proteins, of a homologue of such an amino acid, for example in which the amino acid side chain is extended or shortened by one or two methylene groups and / or a methyl group is replaced by hydrogen, a substituted aromatic a-amino acid, for example a substituted phenylalanine or phenylglycine, in which the substituent is lower alkyl, for example methyl, halogen, for example fluorine, chlorine, bromine or iodine, hydroxy, lower alkoxy, for example methoxy, ⁇ lower alkanoyloxy , for example acetoxy, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, lower alkanoylamino, for example acetylamino or pivaloylamino, lower
• amino acids examples include glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (a-aminovaleric acid), leucine, (H-Leu-OH), isoleucine ( H-Ile-OH), norleucine (a-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (a-amino-y-hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), tyrosine (H- Tyr-OH), 4-nitrophenylalanine, 4-aminophenylalanine, 4-chlorophenylalanine, ß-phenylserine (ß-hydroxyphenylalan
• the amino acid residue A can be N-terminal to increase the stability of the compound of formula I against enzymatic degradation by lower alkyl, e.g. Methyl or ethyl.
• A is preferably the divalent residue of alanine, valine, norvaline, leucine, norleucine, serine, etherified serine, proline, phenylalanine, ß-phenylserine, a-naphthylalanine, cyclohexylalanine, indoline-2-carboxylic acid, 1,2,3,4- Tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, esterified aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, esterified glutamic acid, glutamine, di-lower alkyl glutamine, histidine, lysine, acylated lysine, ornithine or lower alkyl, for example, terminal or acylated ornithine Methyl, substituted.
• the bivalent radical of histidine, and also of serine and alanine, are very particularly preferred as group A.
• Lower alkyl R 2 or R 3 has the meanings given above for lower alkyl R.
• Lower alkyl R 2 is preferably methyl or ethyl.
• Lower alkyl R 3 is preferably isopropyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl or 2-ethylbutyl.
• Hydroxy-lower alkyl R 3 or R 5 is preferably hydroxymethyl or hydroxyethyl and is optionally etherified or esterified by one of the groups specified below for etherified or esterified hydroxy R 4 .
• Cycloalkyl R 3 or R 5 has the meanings given above for cycloalkyl R a or R b and is preferably cyclopentyl or cyclohexyl.
• Cycloalkyl-lower alkyl R 3 and Rs has the meanings given above for cycloalkyl-lower alkyl R a and is preferably cyclohexylmethyl.
• Bicycloalkyl-lower alkyl R 3 or R 5 contains, for example, 6-14, in particular 7-12, carbon atoms and is, for example, methyl or ethyl substituted by the radicals mentioned above for bicycloalkyl R a or R, for example bicyclo [2.2.1] hept-2 -ylmethyl.
• Tricycloalkyl-lower alkyl R 3 or R 5 contains, for example, 9-14, in particular 10-12, carbon atoms and is, for example, methyl or ethyl, preferably 1-adamantylmethyl, substituted by the radicals mentioned above for tricycloalkyl R a or R b .
• Aryl R 3 or R 5 has the meanings given above for aryl R a or R b and is preferably phenyl.
• Aryl-lower alkyl R 3 or Rs has the meanings given above for aryl-lower alkyl R a and is preferably benzyl.
• An etherified hydroxyl group R 4 is preferably etherified by organic residues which can be split off under physiological conditions and which, after the split-off in the concentration in question, provide pharmacologically acceptable breakdown products.
• Etherified hydroxy R 4 is, for example, acyloxy lower alkoxy, in which acyl represents the acyl group of an optionally branched lower alkane carboxylic acid or carbonic acid monoesterified by optionally branched lower alkyl, for example lower alkanoyloxy lower alkoxy such as acetoxymethoxy, 1-acetoxyethoxy, pivaloyloxymethoxy or 1-pivaloyloxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxyoxy AethoxycarbonyloxyHenceoxy, tert-Butoxycarbonyloxymethoxy or I-tert-Butoxycarbonyloxyäthoxy.
• acyl represents the acyl group of an optionally branched lower alkane carboxylic acid or carbonic acid monoesterified by optionally branched lower alkyl
• lower alkanoyloxy lower alkoxy such as acetoxy
• Etherified hydroxy R 4 is also lower alkoxy, for example methoxy or ethoxy, aryloxy, for example phenoxy, or aryl-lower alkoxy, for example benzyloxy.
• Esterified hydroxy R 4 is, for example, aliphatic acyloxy, for example lower alkanoyloxy, such as acetoxy or pivaloyloxy, cycloaliphatic acyloxy, for example cycloalkylcarbonyloxy, such as cyclohexylcarbonyloxy, or aromatic acyloxy, for example benzoyloxy.
• Lower alkyl R 5 has 1-7 C atoms and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or isopentyl. Methyl, isopropyl, isobutyl and tert-butyl are particularly preferred.
• Bicycloalkyl R 5 has the meanings given above for bicycloalkyl R or R b and is preferably a-decahydronaphthyl.
• Tricycloalkyl R 5 has the meanings given above for tricycloalkyl R a or R b and is preferably 1-adamantyl.
• Optionally substituted carbamoyl R 5 is unsubstituted or substituted by one or two lower alkyl or hydroxy-lower alkyl groups and is, for example, carbamoyl, methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, 2-hydroxyethyl or 2-hydroxyethyl-2-hydroxycarbamoyl carbamoyl.
• Optionally substituted amino R 5 is unsubstituted, substituted by one or two lower alkyl groups or by aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or arylmethoxycarbonyl or part of a five- or six-membered heterocycle containing one or two nitrogen atoms and, if desired, an oxygen or sulfur atom and is, for example, amino, methylamino, Ethylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, benzylamino, acetylamino, pivaloylamino, methoxy, ethoxy or tert-butoxycarbonylamino, benzyloxycarbonylamino, 1-pyrrolidinyl, 1-piperidinyl, I-methyl-4-pyridazinyl, 4-morpholinyl or 4-thiomorpholinyl, preferably dimethylamino.
• Optionally substituted hydroxy R 5 is unsubstituted or etherified or esterified by one of the groups mentioned above for etherified or esterified hydroxy R 4 and is, for example, hydroxy, methoxy, ethoxy, acetoxymethoxy, phenoxy, benzyloxy, acetoxy, pivaloyloxy or benzoyloxy.
• Optionally substituted mercapto R 5 is unsubstituted or substituted by lower alkyl, for example methyl or ethyl, aryl, for example phenyl, aryl-lower alkyl, for example benzyl, lower alkanoyl, for example acetyl, or arylcarbonyl, for example benzoyl, and is for example mercapto, methylthio, ethylthio, phenylthio, benzylthio , Acetylthio or benzoylthio.
• lower alkyl for example methyl or ethyl
• aryl for example phenyl, aryl-lower alkyl, for example benzyl, lower alkanoyl, for example acetyl, or arylcarbonyl, for example benzoyl
• Sulfinyl R 5 carries a lower alkyl group, for example methyl or ethyl, an aryl group, for example phenyl, or an aryl lower alkyl group, for example benzyl, and is for example methylsulfinyl, ethylsulfinyl, phenylsulfinyl or benzylsulfinyl.
• Sulfonyl Rs carries a lower alkyl group, e.g. Methyl or ethyl, an aryl group, e.g. Phenyl, or an aryl-lower alkyl group, e.g. Benzyl, and is for example methylsulfonyl, ethylsulfonyl, phenylsulfonyl or benzylsulfonyl, preferably methylsulfonyl.
• Substituted amino R 6 is, for example, an amino group which is substituted by one or optionally two unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radicals having up to and including 18, preferably up to and including 10, carbon atoms or an unsubstituted or substituted, aromatic, heteroaromatic, aromatic- aliphatic or heteroaromatic-aliphatic hydrocarbon radical with up to 18, preferably up to and including 10, carbon atoms is substituted.
• substituted amino R 6 is the remainder of an a-amino acid or its N-substituted, esterified or amidated derivatives.
• An unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radical which substitutes the amino group R 6 is, for example, optionally substituted alkyl having up to 10 C atoms, lower alkenyl or lower alkynyl having up to and including 7 C atoms, or cycloalkyl-lower alkyl having 4-10 C -Atoms. Like lower alkyl R, these radicals can be substituted by one or more of the functional groups mentioned above, and by sulfo.
• lower alkoxy e.g. Methoxy, lower alkanoyloxy, e.g. Acetoxy, substituted or unsubstituted phenyloxy, e.g. Carbamoylphenyloxy or carbamoyl-hydroxy-phenyloxy, carboxy, esterified carboxy, e.g. Lower alkoxycarbonyl, such as methoxycarbonyl or tert-butoxycarbonyl, or a physiologically cleavable esterified carboxy, e.g.
• 1- (lower alkanoyloxy) lower alkoxycarbonyl such as acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or I-propionyloxyethoxycarbonyl
• 1- (lower alkoxycarbonyl-oxy) lower alkoxycarbonyl such as 1- (ethoxycarbonyloxy) ethoxycarbonyl, or a-aminonethoxycarbonyl or amoxonethoxycarbonyl, ) -A-amino-ß-methylbutyryloxymethoxycarbonyl, carbamoyl, substituted or unsubstituted lower alkylcarbamoyl, for example Hydroxy lower alkyl carbamoyl such as 2-hydroxyethyl carbamoyl or tris (hydroxymethyl) methyl carbamoyl, amino, lower alkyl amino, e.g.
• oxo-heterocyclyl e.g. 1-piperidinyl, 4-morpholinyl or 2-oxo-1-pyrrolidinyl, or sulfo is preferred.
• An aromatic or aromatic-aliphatic hydrocarbon radical in a group R 6 preferably has the same meanings as mentioned under aryl R or R b or aryl-lower alkyl R a and is, for example, phenyl or phenyl-lower alkyl.
• residues can be found in aromatics e.g. by lower alkyl, e.g. Methyl or ethyl, hydroxy, etherified hydroxy, e.g. Lower alkoxy such as methoxy or tert-butoxy, esterified hydroxy e.g. Lower alkanoyloxy such as acetoxy or halogen e.g. Fluorine or chlorine, carboxy, esterified carboxy, e.g. Lower alkoxycarbonyl such as tert-butoxycarbonyl, carbamoyl, amino, lower alkylamino e.g. Methylamino, di-lower alkylamino, e.g. Dimethylamino, acylated amino, e.g. Niederalkoxycarbonylamino, such as tert-butoxycarbonylamino, and substituted by nitro.
• lower alkyl e.g. Methyl or ethyl
• Lower alkyl in a radical phenyl-lower alkyl can be substituted by the same substituents as alkyl in a radical R 6 .
• a heteroaromatic or heteroaromatic-aliphatic hydrocarbon radical in a group R 6 preferably has the same meanings as mentioned under Heteroaryl Rund R or heteroaryl-lower alkyl R and is, for example, pyridyl-lower alkyl, for example 2-, 3- or 4-pyridylmethyl, imidazolyl-lower alkyl, for example 2- (4- Imidazolyl) ethyl or 2- (2- [4-imidazolyl] ethylamino) ethyl, or indolyl lower alkyl, for example 3-indolylmethyl or 2- (3-indolyl) ethyl.
• Substituted amino R 6 is preferably alkylamino, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n -Octyl- or n-decylamino, di-lower alkylamino, for example dimethylamino or diethylamino, hydroxy-lower alkylamino, for example 2-hydroxyethylamino, 1-hydroxybut-2-ylamino, 5-hydroxypentylamino or tris (hydroxymethyl) methylamino, di- (hydroxy-lower alkyl) amino , for example di- (2-hydroxyethyl) amino, lower alk oxyniederalkylamino, for example 2-Methoxyäthylamino, lower alkanoyl o xyniederalky
• di- (methylcarbamoyl) -methylamino di- (hydroxy-lower alkylcarbamoyl) -methylamino, e.g. di- (2-hydroxyethylcarbamoyl) -methylamino, or bis- (diniederalkylcarbamoyl) -methylamino, e.g.
• tert-butoxycarbonylamino and / or by nitro mono - or is substituted several times for example phenylamino, 2-, 3- or 4-methylphenylamino, 4-hydroxyphenylamino, 4-methoxyphenylamino, 2,3-, 2,4- or 2,5-dimethoxyphenylamino, 4-chlorophenylamino, 2-, 3- or 4-carboxyphenylamino, 2-, 3- or 4-methoxy- or tert-butoxy-carbonylphenylamino, 2-, 3- or 4-carbamoylphenylamino, 4-aminophenylamino, 4-tert-butoxycarbonylaminophenylamine o or 4-nitrophenylamino, furthermore, for example, benzylamino, 4-methylbenzylamino, 4-methoxybenzylamino, 2-, 3- or 4-carboxybenzylamino, 2-, 3- or 4-tert-butoxycarbonylbenzylamino,
• Salts are primarily the pharmaceutically usable, non-toxic salts of compounds of the formula I.
• Such salts are formed, for example, by compounds of the formula I with an acidic group, for example a carboxy group, and are primarily suitable alkali metal, for example sodium or potassium, or alkaline earth metal salts, for example magnesium or calcium salts, furthermore zinc salts or ammonium salts such salts, which with organic cal amines, such as mono-, di- or trialkylamines optionally substituted by hydroxy, are formed, for example with diethylamine, di- (2-hydroxyethyl) amine, triethylamine, N, N-dimethyl-N- (2-hydroxyethyl) amine , Tri- (2-hydroxyethyl) amine or N-methyl-D-glucamine.
• organic cal amines such as mono-, di- or trialkylamines optionally substituted by hydroxy
• the compounds of formula 1 with a basic group can form acid addition salts, for example with inorganic acids, for example hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic or sulfonic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, the mentioned hereinbefore also with amino acids, such as further ⁇ -amino acids, as well as with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disul
• inorganic acids
• the compounds of the present invention have enzyme inhibitory effects; in particular, they inhibit the action of the natural enzyme renin.
• the latter enters the blood from the kidneys and there causes the cleavage of angiotensinogen to form the decapeptide angiotensin I, which is then broken down in the lungs, kidneys and other organs to form the octapeptide angiotensin II.
• the latter increases blood pressure both directly through arterial constriction and indirectly through the release of the sodium ion-retaining hormone aldosterone from the adrenal glands, which is associated with an increase in the extracellular fluid volume. This increase is due to the effect of angiotensin II itself or the heptapeptide angiotensin III formed therefrom as a cleavage product attributed.
• Inhibitors of the enzymatic activity of renin reduce the formation of angiotensin I. As a result, a lower amount of angiotensin II is produced.
• the reduced concentration of this active peptide hormone is the direct cause of the blood pressure-lowering effect of renin inhibitors.
• renin inhibitors The effect of renin inhibitors is demonstrated experimentally using in vitro tests, among other things, whereby the reduction in the formation of angiotensin I is measured in various systems (human plasma, purified human renin together with synthetic or natural renin substrate).
• in vitro test is used: An extract of human renin from the kidney (0.5 mGU [milli-gold leaf units] / ml) is 1 molar for one hour at 37 ° C.
• angiotensin I formed is determined in a radioimmunoassay.
• the inhibitors according to the invention are added to the incubation mixture in different concentrations.
• the IC 50 is the concentration of the respective inhibitor that reduces the formation of angiotensin I by 50%.
• the compounds of the present invention show inhibitory effects in the in vitro systems at minimum concentrations of about 10 -7 to about 10 -10 mol / l.
• Renin inhibitors cause a drop in blood pressure in salt-depleted animals.
• Human renin is different from renin of other species. Primates (marmosets, Callithrix jacchus) are used to test inhibitors of human renin because human renin and primate renin are largely homologous in the enzymatically active region.
• the test compounds are tested on normotensive marmosets of both sexes with a body weight of about 300 g, which are conscious. Blood pressure and heart rate are measured with a catheter in the femoral artery. The endogenous release of renin is by intravenous injection of furosemide (5 mg / kg) excited.
• test substances are administered either via a catheter in the lateral tail vein by a single injection or by continuous infusion or orally directly into the stomach as a solution or suspension and their effect on blood pressure and heart rate is evaluated.
• the compounds of the present invention are effective in the described in vivo test at doses from about 0.1 to about 1.0 mg / kg po and at doses from about 1.0 to about 10 mg / kg po.
• the compounds of the present invention can be used as antihypertensives, further for the treatment of heart failure.
• the invention relates in particular to compounds of the formula I in which R 1 is an acyl group of a saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aromatic-aliphatic group substituted by a thio, sulfinyl or sulfonyl group and optionally by further heteroatom-containing groups , heteroaromatic or heteroaromatic-aliphatic carboxylic acid with the exception of the optionally N-substituted natural amino acid methionine,
• A an optionally N-alkylated a-amino acid residue which is connected N-terminally to R 1 and C-terminally to the group -NR 2 -, R 2 hydrogen or lower alkyl, R 3 hydrogen, lower alkyl, hydroxy-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, bicycloalkyl-lower alkyl, tricycloalkyl-
• R 1 is a radical of the formula wherein R is unsubstituted or substituted lower alkyl, e.g. methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-phenoxyethyl, 2-acetoxyethyl, carboxymethyl, 2-carboxyethyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl, 2- Aethoxycarbonyläthyl, Carbamoylmethyl, 2-Carbamoyläthyl, 2-Aminoäthyl, 2-Dimethylaminoäthyl, 2-Morpholinoäthyl, 2-Piperidinoäthyl, 2-Benzyloxycarbonylaminoäthyl, 2-tert-Butoxycarbonylaminoäthyl, 2-oxopropy
• benzyl 2-phenylethyl or a- or ß-naphthylmethyl, aryl-lower alkenyl, e.g. styryl or 3-phenylallyl, unsubstituted or substituted heteroaryl, e.g.
• A is a bivalent residue of an a-amino acid, for example a natural o-amino acid with the L configuration, as normally found in proteins, of a homologue of such an amino acid, for example in which the amino acid side chain is extended or shortened by one or two methylene groups and / or a methyl group is replaced by hydrogen, a substituted aromatic a-amino acid, for example a substituted phenylalanine or phenylglycine, in which the substituent is lower alkyl, for example methyl, halogen, for example fluorine, chlorine, bromine or iodine, hydroxy, lower alkoxy, for example methoxy, lower alkanoyloxy, for example acetoxy, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, lower alkanoylamino, for example acetylamino or pivaloylamino, lower alkoxycarbon
• R 2 is hydrogen or lower alkyl, for example methyl
• R 3 is lower alkyl, for example isopropyl or isobutyl
• cycloalkyl for example cyclohexyl, cycloalkyl-lower alkyl, for example cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or cycloheptylmethyl, tricycloalkyl-lower alkyl, for example l-adamantylmethyl, phenyl, lower alkyl , R 4 hydroxy, R 5 lower alkyl, for example methyl, isopropyl, isobutyl or tert-butyl, cycloalkyl, for example cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, for example cyclohexylmethyl, bicycloalkyl, for example a-decahydronaphthyl, tricyclo
• benzyl carbamoyl or lower alkylcarbamoyl, e.g. methylcarbamoyl, di-lower alkylamino, e.g. dimethylamino, hydroxy, lower alkoxy, e.g. methoxy, lower alkylthio, e.g. methylthio, or lower alkylsulfonyl, e.g.
• methylsulfonyl, and R 6 alkylamino with 1 to 10 carbon atoms for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl , n-octyl- or n-decylamino, di-lower alkylamino, for example dimethylamino or diethylamino, hydroxy-lower alkylamino, for example 2-hydroxyethylamino, 1-hydroxybut-2-ylamino, 5-hydroxypentylamino or tris (hydroxymethyl) methylamino, di- (hydroxy-lower alkyl) - amino, for example di- (2-hydroxyethyl) amino, lower alkoxy-lower alkylamino, for example 2-methoxyethylamino, lower alkanoyloxy-
• R 1 is a radical of the formula wherein R a is unsubstituted or substituted by hydroxy, lower alkoxy, phenoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl or carbamoyl, for example methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-phenoxyethyl, 2-acetoxyethyl, carboxymethyl , 2-carboxyethyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, carbamoylmethyl or 2-carbamoylethyl, cycloalkyl, for example cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, for example cyclopropylmethyl, cyclopent
• R z is hydrogen or lower alkyl, for example methyl
• R 3 is lower alkyl, for example isopropyl or isobutyl
• cycloalkyl-lower alkyl for example cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or cycloheptylmethyl, or tricycloalkyl-lower alkyl, for example 1-adamantylmethyl
• R 4 hydroxy and Rs loweralkyl for example methyl, isopropyl or tert-butyl
• cycloalkyl for example cyclopentyl or cyclohexyl
• cycloalkyl-lower alkyl for example cyclohexylmethyl, 1-adamantyl, benzyl, carbamoyl or lower alkylcarbamoyl, for example methylcarbamoyl, di-lower alkylamino, for example dimethylamino, hydroxy,
• R 1 is a radical of the formula
• R a is unsubstituted or substituted by hydroxy, lower alkoxy, phenoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl or carbamoyl, for example methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-phenoxyethyl, 2-acetoxyethyl, carboxymethyl , 2-carboxyethyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, carbamoylmethyl or 2-carbamoylethyl, cycloalkyl, for example cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, for example cyclopropylmethyl, cyclopent
• R 2 hydrogen, R 3 lower alkyl, for example isobutyl, or cycloalkyl-lower alkyl, for example cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or
• R 4 hydroxy, R 5 lower alkyl for example isopropyl, hydroxy, lower alkoxy, for example methoxy, lower alkylthio, for example methylthio, or lower alkylsulfonyl, for example methylsulfonyl, and
• R 6 lower alkylamino with 1-7 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or isopentyl-amino, di-lower alkylamino, for example dimethylamino, hydroxy lower alkylamino, for example 2-hydroxyethylamino, 1-hydroxybut-2-ylamino or 5-hydroxypentylamino, carboxyalkylamino or amino-carboxyalkylamino, in which the carboxy radical is not in the 1-position of the alkyl radical, for example 4-carboxy-n-butylamino, 7- Carboxy-n-heptylamino or 8-carboxy-n-octylamino or 5-amino-5-carboxy-n-pentylamino, lower alkoxycarbonylalkylamino or acylamino-lower alk
• R 1 is a radical of the formula wherein R a unsubstituted or substituted by hydroxy or lower alkoxy lower alkyl, for example methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl or 2-methoxyethyl, phenyl, benzyl or unsubstituted or substituted by oxido or lower alkyl with 1 or 2 nitrogen atoms, for example 2- or 4-imidazolyl, 1-methyl-2-imidazolyl, 2-, 3- or 4-pyridyl, 1-oxido-2-, 3- or 4-pyridinio or 2-pyrimidinyl, R cyclohexyl or phenyl, m 0 , 1 or 2, n 1, p 0 and q represent 1 or 2, A is the divalent residue of the amino acid histidine, R 2 is hydrogen, R 3 is cyclohexylmethyl, R 4 is hydroxy
• R 1 is a radical of the formula wherein R a is lower alkyl, for example methyl, ethyl, isopropyl or tert-butyl, phenyl, 2-pyridyl, hydroxy, lower alkylamino, for example methylamino or isopropylamino, di-lower alkylamino, for example dimethylamino or diethylamino, or pyrrolidino, R b is phenyl, m 2, n 1, p 0 and q 1, A is the divalent radical of the amino acid alanine, serine or histidine, R 2 is hydrogen, R 3 is cycloalkyl-lower alkyl, for example cyclopentylmethyl, cyclohexylmethyl, 2- Cyclohexylethyl or cycloheptylmethyl, R 4 hydroxy, R 5 methyl, isopropyl, hydroxy, me
• the invention relates first of all to the compounds mentioned in the examples and their pharmaceutically acceptable salts, in particular
• R 1 is a radical of the sub-formula Ia, in which R a is tert-butyl, R b is phenyl, m 2, n 1, p 0 and q 1
• A is the divalent radical of the amino acid L-histidine
• R 2 is hydrogen
• R 3 is cyclohexylmethyl
• R 4 is hydroxy
• R 5 isopropyl
• R 6 is n-butylamino and the carbon atoms bearing the radicals R 3 , R 4 and R 5 and the methine carbon atom of the sub-formula Ia are the S- Have configuration, and their pharmaceutically acceptable salts
• R 3 is a radical of the sub-formula la, in which R a is tert-butyl, R b is phenyl, m 2, n 1, p 0 and q 1,
• A is the divalent radical of the amino acid L-histidine
• R 2 is hydrogen
• R 3 is cyclohexylmethyl
• R 4 is hydroxy
• R 5 is methyl
• R 6 is methylamino
• the carbon atoms bearing the radicals R 3 and R 4 and the methine carbon atom of sub-formula Ia are the S configuration and that is the rest C 5 atoms bearing R 5 have the R configuration and their pharmaceutically acceptable salts
• R 1 is a radical of the sub-formula Ia, in which R a is tert-butyl, R b is phenyl, m 2, n 1, p 0 and q 1
• A is the divalent radical of the amino acid L-alanine
• R 2 hydrogen, R 3 cyclohexylmethyl, R 4 hydroxy, R 5 isopropyl and R 6 n-butylamino mean and the carbon atoms bearing the radicals R 3 , R 4 and R 5 and the methine carbon atom of the partial formula Ia have the S configuration, and their pharmaceutically acceptable salts,
• R 1 is a radical of sub-formula Ia, in which R a t er t-butyl, R b is phenyl, m 2, n 1, p 0 and q 1
• A is the divalent radical of the amino acid L-histidine
• R 2 is hydrogen
• R 3 is cycloheptylmethyl
• R 4 is hydroxy
• R 5 isopropyl
• R 6 is n-butylamino and the carbon atoms bearing the radicals R 3 , R 4 and R 5 and the methine carbon atom of sub-formula Ia are S configuration, and their pharmaceutically acceptable salts
• R 1 is a radical of sub-formula Ia, in which R a t er t-butyl, R b is phenyl, m 2, n 1, p 0 and q 1
• A is the divalent radical of the amino acid L-histidine
• R 2 is hydrogen
• R 3 is cyclohept
• R 1 is a radical of the sub-formula Ia, in which R a t er t-butyl, R b is phenyl, m 2, n 1, p 0 and q 1
• A is the divalent radical of the amino acid L-histidine
• R 2 is hydrogen
• R 3 is cyclohexylmethyl
• R 4 is hydroxy
• R 5 isopropyl
• R & methylamino and the C atoms carrying the radicals R 3 , R 4 and Rs and the methine C atom of sub-formula Ia have the S configuration , and their pharmaceutically acceptable salts.
• the invention also relates to the compounds other than compounds of the formula I (by-product) obtainable by any of the processes mentioned above, and to compounds of the formula I and their salts which are prepared by a process other than one of those mentioned above.
• Fragments of a compound of the formula I with a terminal carboxy group which can be condensed with a fragment which is complementary to the compound of the formula I to form an amide bond are, for example, compounds of the formulas R I -OH, R I -A-OH or the activated esters or reactive anhydrides derived from these compounds, and also reactive cyclic amides.
• the reactive acid derivatives can also be formed in situ.
• Activated esters are, in particular, unsaturated esters on the linking carbon atom of the esterifying radical, for example of the vinyl ester type, such as vinyl esters (obtainable, for example, by transesterifying a corresponding ester with vinyl acetate; method of the activated vinyl ester), carbamoyl vinyl esters (obtainable, for example, by treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method) or 1-lower alkoxyvinyl ester (obtainable, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or esters of the amidino type, such as N, N'-disubstituted amidino esters (obtainable, for example, by treatment the corresponding acid with a suitable N, N'-disubstituted carbodiimide, for example N, N'-dicyclohexylcarbodiimide; carbodiimide method)
• Anhydrides of acids can be symmetrical or preferably mixed anhydrides of these acids, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester about the corresponding hydrazide and its treatment with nitrous acid; azide method), anhydrides with carbonic acid half-esters, for example carbonic acid lower alkyl half-esters (obtainable, for example, by treating the corresponding acid with chloroformic acid lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1- Aethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline; method of mixed 0-alkyl carbonic anhydrides), anhydrides with dihalogenated, especially
• anhydrides with organic acids such as mixed anhydrides with organic carboxylic acids (obtainable for example by treating the corresponding acid with an optionally substituted one Lower alkane or phenyl-lower alkane carboxylic acid halide, for example phenylacetic acid, pivalic acid or trifluoroacetic acid chloride; Method of mixed carboxylic acid anhydrides) or with organic sulfonic acids (obtainable, for example, by treating a salt, such as an alkali metal salt, the corresponding acid with a suitable organic sulfonic acid halide, such as lower alkane or aryl, for example methane or p-toluenesulfonic acid chloride; method of mixed sulfonic acid anhydrides) , as well as symmetrical anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a car
• Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, e.g. Imidazole (obtainable e.g. by treating the corresponding acid with N, N'-carbonyldiimidazole; imidazole method), or pyrazoles, e.g. 3,5-dimethylpyrazole (obtainable e.g. via the acid hydrazide by treatment with acetylacetone; pyrazolide method).
• imidazoles e.g. Imidazole (obtainable e.g. by treating the corresponding acid with N, N'-carbonyldiimidazole; imidazole method)
• pyrazoles e.g. 3,5-dimethylpyrazole (obtainable e.g. via the acid hydrazide by treatment with acetylacetone; pyrazolide method).
• Fragments complementary to the compound of the formula I having a free amino group are, for example, depending on the meaning of R & a primary or secondary amine, and furthermore compounds of the formulas or
• the amino group participating in the reaction in a fragment which is complementary to a compound of the formula I is preferably in free form, in particular if the carboxy group reacting therewith is in a reactive form; but it can also be derivatized itself, for example by reaction with a phosphite such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite.
• a phosphite such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite.
• a derivative such a complementary fragment with an amino group is, for example, a carbamic acid halide or an isocyanate, the amino group participating in the reaction being substituted by halogen carbonyl, for example chlorocarbonyl, or modified as an isocyanate group, in the latter case only compounds of the formula I which are accessible bear a hydrogen atom on the nitrogen atom of the amide group formed by the reaction.
• the complementary fragment with an amino group is an amine mono- or disubstituted by lower alkyl or aryl-lower alkyl, then a corresponding urea compound is also a reactive derivative. For example, heating equimolar amounts of this urea compound and the component with free carboxy group gives corresponding compounds of the formula I. If the complementary fragment is dimethylamine, then dimethylformamide is also a reactive derivative.
• Functional groups in starting materials can be protected by suitable protective groups, as is customary in the synthesis of peptide compounds, but also of cephalosporins and penicillins be used.
• protective groups can already be present in the preliminary stages and are intended to protect the functional groups in question against undesired side reactions such as acylations, etherifications, esterifications, oxidations, solvolysis, etc.
• Protective groups can also be present in the end products.
• Compounds of formula I with protected functional groups can have a higher metabolic stability than the corresponding compounds with free functional groups.
• a carboxy group is e.g. protected as an ester group that is selectively cleavable under mild conditions.
• a carboxy group protected in esterified form is esterified primarily by a lower alkyl group which is branched in the 1-position of the lower alkyl group or substituted in the 1- or 2-position of the lower alkyl group by suitable substituents.
• a protected carboxy group which is esterified by a lower alkyl group which is branched in the 1-position of the lower alkyl group is, for example, tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, or arylmethoxycarbonyl with one or two aryl radicals, wherein aryl is unsubstituted or e.g. by lower alkyl, e.g. tert-lower alkyl such as tert-butyl, lower alkoxy, e.g. Methoxy, hydroxy, halogen, e.g.
• Chlorine, and / or nitro means mono-, di- or tri-substituted phenyl, for example benzyloxycarbonyl, benzyloxycarbonyl substituted by the substituents mentioned, e.g. 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted by said substituents, e.g. Di- (4-methoxyphenyl) methoxycarbonyl.
• a protected carboxy group which is esterified by a lower alkyl group which is substituted in the 1- or 2-position of the lower alkyl group by suitable substituents is, for example, 1-lower alkoxy lower alkoxycarbonyl, for example methoxymethoxycarbonyl, 1-methoxyathoxycarbonyl or 1-ethoxyethoxycarbonyl, 1-lower alkylthione lower alkoxycarbonyl, for example 1 -Methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, for example phenacyloxycarbonyl, 2-halogeno lower alkoxycarbonyl, for example 2,2,2-trichloroethoxy carbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, and 2-tri-lower alkylsilyl-lower alkoxycarbonyl, for example 2-trimethylsilyl-ethoxycarbonyl.
• a carboxy group can also be protected as an organic silyloxycarbonyl group.
• An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, e.g. Trimethylsilyloxycarbonyl.
• the silicon atom of the silyloxycarbonyl group can also be substituted by two lower alkyl groups, e.g. Methyl groups, and the amino group or the carboxy group of a second molecule of the formula I can be substituted. Connections with such protective groups can e.g. with dimethylchlorosilane as a silylating agent.
• a protected carboxy group is preferably tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl.
• amino group can e.g. be protected in the form of an acylamino, arylmethylamino, etherified mercaptoamino or silylamino group or as an azido group.
• acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, in particular a lower alkane carboxylic acid optionally substituted, for example by halogen or aryl, or optionally substituted, for example, by halogen, lower alkoxy or nitro, or preferably a carbonic acid semiester.
• Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halogenated lower alkanoyl, for example 2-haloacetyl, such as 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2 , 2-trichloroacetyl, optionally substituted, for example, by halogen, lower alkoxy or nitro, benzoyl, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position , for example tert-lower alkoxycarbonyl, such as tert-Butoxycarbonyl, arylmethoxycarbonyl with one or two aryl radicals, optionally, for example by lower alkyl, for example
• An arylmethylamino group is e.g. Mono-, di- or especially triphenylmethylamino, e.g. Benzyl, diphenylmethyl or tritylamino.
• the etherified mercapto group is primarily substituted arylthio, e.g. 4-nitrophenylthio.
• a silylamino group is, for example, a tri-lower alkylsilylamino group, e.g. Trimethylsilylamino.
• the silicon atom of the silylamino group can also be replaced only by two lower alkyl groups, e.g. Methyl groups, and the amino group or carboxyl group of a second molecule of the formula I can be substituted. Connections with such protective groups can e.g. with dimethylchlorosilane as a silylating agent.
• Preferred amino protecting groups are acyl residues of carbonic acid semiesters, especially tert-butoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 2-halogeno-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, also trityl and formyl.
• benzyloxycarbonyl e.g. 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 2-halogeno-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, also trityl and formyl.
• a hydroxy group can be replaced, for example, by a halogen, e.g. Chlorine, substituted lower alkanoyl group, e.g. 2,2-dichloroacetyl, or, in particular, be protected by an acyl radical of a carbonic acid semester called for protected amino groups.
• a preferred hydroxy protecting group is, for example, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl.
• a hydroxy group can also be substituted by tri-lower alkylsilyl, e.g.
• 2-tetrahydrofuryl or 2-tetrahydropyranyl or a corresponding thia analogue
• 1-phenyl-lower alkyl e.g. Benzyl, diphenylmethyl or trityl
• the phenyl radicals being, for example, halogen, e.g. Chlorine, lower alkoxy, e.g. Methoxy, and / or nitro may be substituted.
• two adjacent hydroxyl groups may be protected by a preferably substituted methylene group, e.g. by lower alkylidene, e.g. Isopropylidene, cycloalkylidene, e.g. Cyclohexylidene, or benzylidene.
• lower alkylidene e.g. Isopropylidene
• cycloalkylidene e.g. Cyclohexylidene
• benzylidene e.g.
• a mercapto group, such as in cysteine, can be protected in particular by S-alkylation with optionally substituted alkyl radicals, silylation, thioacetal formation, S-acylation or by the formation of asymmetric disulfide groups.
• Preferred mercapto protecting groups are, for example, benzyl, such as 4-methoxybenzyl, optionally substituted in the phenyl radical, for example by methoxy or nitro, optionally substituted on the phenyl radical, for example diphenylmethyl, for example substituted by methoxy, such as 4,4'-dimethoxydiphenylmethyl, triphenylmethyl, trimethylsilyl, benzylthiomethyl, 2-tetrahydropyrany ,
• a sulfo group may, for example, be lower alkyl, e.g. Methyl or ethyl, be protected by phenyl or as sulfonamide, for example as imidazolide.
• the condensation for the production of the amide bond can be carried out in a manner known per se, for example as in standard works such as "Houben-Weyl, Methods of Organic Chemistry", 4th edition, volume 15 / II, Georg Thieme Verlag, Stuttgart 1974, "The Peptides "(Ed. E. Gross and J. Meienhofer), Vol. 1 and 2, Academic Press, London and New York, 1979/1980, or M. Bodanszky,” Principles of Peptide Synthesis “, Springer-Verlag, Berlin 1984, described.
• the condensation can be carried out in the presence of one of the customary condensation agents.
• Common condensing agents are e.g. Carbodiimides, for example diethyl, dipropyl, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or especially dicyclohexylcarbodiimide, furthermore suitable carbonyl compounds, for example carbonyldiimidazole, 1,2-oxazolium compounds, e.g. 2-ethyl-5-phenyl-l, 2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e.g.
• 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline also activated phosphoric acid derivatives, e.g. Diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridat, bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride or 1-benzotriazolyloxy-tris (dimethylamino) -phosphonium hexafluorophosphate.
• phosphoric acid derivatives e.g. Diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridat, bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride or 1-benzotriazolyloxy-tris (dimethylamino) -phosphonium hexafluorophosphate.
• an organic base is added, e.g. a tri-lower alkyl amine with bulky residues, e.g. Ethyldiisopropylamine, or a heterocyclic base, e.g. Pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine.
• a tri-lower alkyl amine with bulky residues e.g. Ethyldiisopropylamine
• a heterocyclic base e.g. Pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine.
• the condensation of acid anhydrides with amines can e.g. in the presence of inorganic carbonates, e.g. Alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate).
• inorganic carbonates e.g. Alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate).
• the condensation is preferably carried out in an inert, polar, aprotic, preferably anhydrous, solvent or solvent mixture, for example in a carboxamide, e.g. Formamide or dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, cyclic ether, e.g. Tetrahydrofuran, an ester, e.g. Ethyl acetate, or a nitrile, e.g. Acetonitrile, or in mixtures thereof, optionally at reduced or elevated temperature, e.g. in a temperature range from about -40 ° C to about + 100 ° C, preferably from about -10 ° C to about + 50 ° C, and optionally under an inert gas, e.g. Nitrogen atmosphere.
• a carboxamide e.g. Formamide or dimethylformamide
• Reactive acid derivatives can also be formed in situ. So you can e.g. Form N, N'-disubstituted amidino esters in situ by mixing the mixture of the free carboxy group fragment and the complementary amino group fragment in the presence of a suitable disubstituted carbodiimide, e.g. Dicyclohexylcarbodiimid, implemented. Furthermore, amino or amido esters of such acids can be formed in the presence of the amino component to be acylated by mixing the mixture of the corresponding acid and amino starting materials in the presence of a disubstituted carbodiimide, e.g. Dicyclohexylcarbodiimide, and an N-hydroxylamine or N-hydroxyamide, e.g.
• a suitable disubstituted carbodiimide e.g. Dicyclohexylcarbodiimid
• amino or amido esters of such acids can be formed in the presence of the amino component to be acylated by mixing the mixture
• N-hydroxybenzotriazole N-hydroxysuccinimide or N-hydroxy-norbornan-2,3-dicarboximide, optionally in the presence of a suitable base, e.g. 4-dimethylaminopyridine, N-methylmorpholine or ethyldiisopropylamine.
• a suitable base e.g. 4-dimethylaminopyridine, N-methylmorpholine or ethyldiisopropylamine.
• the condensation of a carboxylic acid R I -A-OH with the corresponding fragment complementary to the compound of the formula I with a free amino group can also be achieved in a manner known per se with the aid of enzymes, for example as described by H.-D. Jakubke et al. in Angewandte Chemie 97, 79 (1985).
• suitable enzymes are thermolysin, carboxypeptidase Y, papain, chymotrypsin, trypsin or pepsin.
• the reaction is preferably carried out in water or in mixtures of water with organic solvents, for example with lower alkanols, such as ethanol, dimethylformamide, dimethyl sulfoxide, ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, acetone, acetonitrile or polyalcohols, for example ethylene glycol, di- , Tri- or poly-ethylene glycol, but also with immiscible organic solvents, for example methylene chloride or ethyl acetate, at a pH of 5 to 8, preferably around the neutral point, at temperatures between 0 ° C. and 50 ° C.
• organic solvents for example with lower alkanols, such as ethanol, dimethylformamide, dimethyl sulfoxide, ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, acetone, acetonitrile or polyalcohol
• the solvents and the reaction conditions are preferably chosen so that the desired compound precipitates or is extracted into the immiscible organic phase and is thus removed from the reaction equilibrium. It is also possible to carry out the condensation with enzymes immobilized on a suitable carrier, as mentioned above, in the organic solvents mentioned in a mixture with a little water.
• Suitable reducing agents for reducing the keto group in a compound of the formula II are those which, under the reaction conditions of the process, selectively or more rapidly reduce an isolated keto group than the amide groups present in compounds of the formula I.
• suitable borohydrides such as alkali metal borohydrides, in particular sodium borohydride, lithium borohydride or sodium cyanoborohydride, furthermore zinc borohydride, or suitable aluminum hydrides, such as alkali metal low p ralkoxyaluminium hydrides with bulky residues, for example lithium tris-tert-butoxyaluminium hydride.
• the reduction can also be carried out with hydrogen in the presence of suitable heavy metal catalysts, e.g. Raney nickel or platinum or palladium catalysts, e.g. Platinum or palladium activated carbon, or according to Meerwein-Ponndorf-Verley with the aid of aluminum alkanolates, preferably aluminum 2-propanolate or ethanolate.
• suitable heavy metal catalysts e.g. Raney nickel or platinum or palladium catalysts, e.g. Platinum or palladium activated carbon, or according to Meerwein-Ponndorf-Verley with the aid of aluminum alkanolates, preferably aluminum 2-propanolate or ethanolate.
• the reduction can preferably be carried out with stoichiometric amounts or a reasonable excess of the reducing agent in an inert solvent at temperatures between -80 ° C and the boiling point of the solvent, preferably between -20 ° C and + 100 ° C, if necessary under protective gas, e.g. Nitrogen or argon.
• protective gas e.g. Nitrogen or argon.
• An excess of the reducing agent is particularly necessary if it is also mixed with the solvent, e.g. the protons of a protic solvent.
• polar, protic solvents e.g. Methanol, ethanol or isopropanol
• the polar, aprotic solvents mentioned under process a e.g. Tetrahydrofuran.
• a metal radical -M for example -Li or -MgHal, e.g. -MgCl, -MgBr or -MgJ.
• reaction of a compound of formula III with a compound of formula IV is carried out in a conventional manner in an anhydrous, inert, aprotic solvent, e.g. in an ether such as diethyl ether or tetrahydrofuran, or a hydrocarbon such as benzene or toluene, or mixtures thereof, optionally with cooling, especially after the start of the reaction, e.g. to about -30 ° C, or with heating, e.g. up to the boiling temperature of the reaction mixture, optionally in an inert gas, e.g. Nitrogen atmosphere.
• a preferred embodiment of the process is the reaction of the aldehyde of the formula III with an excess of the lithium compound of the formula IV.
• the addition product is hydrolysed with solvents which supply H + ions, for example water (ice-water mixture) or dilute, aqueous acids, for example dilute mineral acids, such as dilute, aqueous sulfuric acid, or dilute organic acids, for example dilute, aqueous acetic acid.
• solvents which supply H + ions, for example water (ice-water mixture) or dilute, aqueous acids, for example dilute mineral acids, such as dilute, aqueous sulfuric acid, or dilute organic acids, for example dilute, aqueous acetic acid.
• reaction of a compound of formula III can also be carried out with a compound of formula IV prepared in situ, which is e.g. from the corresponding halide, e.g. Chloride, by reaction with a metalating agent, e.g. Magnesium, lithium or tert-butyllithium.
• a metalating agent e.g. Magnesium, lithium or tert-butyllithium.
• the nucleofugic leaving group X is, in particular, hydroxy esterified with a strong inorganic or organic acid, such as with a mineral acid, for example halogen water Substance acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or halogenosulfuric acid, for example fluorosulfuric acid, with a strong organic sulfonic acid, such as a lower alkanesulfonic acid optionally substituted, for example by halogen, such as fluorine, or an aromatic sulfonic acid, for example one optionally substituted by lower alkyl, such as methyl , Halogen, such as bromine and / or nitro substituted benzenesulfonic acid, for example a methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid, or hydroxy esterified with hydrochloric acid.
• a strong inorganic or organic acid such as with
• an alcohol for example methanol or ethanol
• R 4 etherified hydroxy
• the reaction conditions are preferably selected such that the reaction proceeds essentially as a second-order nucleophilic substitution (S N 2).
• S N 2 a second-order nucleophilic substitution
• the reaction with a hydroxide-containing base is preferably carried out in water, to which an organic solvent, for example ethanol, tetrahydrofuran or acetone, is optionally added as a solubilizer, and the reaction with an alcohol in an excess of this alcohol, optionally in the presence of one of the polar aprotic solvents mentioned above , carried out.
• the substitution reaction is optionally carried out at a reduced or elevated temperature, for example in a temperature range from about -40 ° C. to about + 100 ° C, preferably from about -10 ° C to about + 50 ° C, and if appropriate under an inert gas, for example nitrogen atmosphere carried out.
• a compound of the formula VI can be converted into a compound of the formula 1 by a Ritter reaction or by means of carboxylic ester imide salts.
• the nitriles are reacted in the presence of a strong acid, for example 85-90% sulfuric acid, or else polyphosphoric acid, hydrogen fluoride, formic acid, boron trifluoride or other Lewis acids, but not aluminum chloride, with compounds which are in the acidic Can form medium carbenium ions, e.g. with olefins, such as propylene, or alcohols, such as benzyl alcohol, usually without solvents or, for example, in glacial acetic acid.
• a strong acid for example 85-90% sulfuric acid, or else polyphosphoric acid, hydrogen fluoride, formic acid, boron trifluoride or other Lewis acids, but not aluminum chloride
• compounds which are in the acidic Can form medium carbenium ions e.g. with olefins, such as propylene, or alcohols, such as benzyl alcohol, usually without solvents or, for example, in glacial acetic acid.
• a nitrile of the formula VI is reacted with an olefin and mercury (II) nitrate, and the organo mercury compound is then reduced to an N-substituted compound of the formula I with sodium borohydride.
• Acid-catalyzed, preferably hydrogen chloride-catalyzed, addition of alcohols to the nitriles of the formula VI gives carboxylic ester imides which, by thermal rearrangement at temperatures above about 80 ° C., give amides of the formula I.
• reducing agents which, under the reaction conditions of the process, selectively or faster reduce the epoxy group than the existing amide groups and open the epoxide in such a way that a sufficiently large and as large a proportion of the reaction products carries the newly formed hydroxyl group in the position corresponding to Formula 1.
• selective reducing agents are lithium borohydride or sodium cyanoborohydride / boron trifluoride etherate.
• the reaction can be carried out, for example, by adding a solution of boron trifluoride etherate to 1 mol of the compound of the formula VII and an excess, for example 1.4-3 mol, of sodium cyanoborohydride in tetrahydrofuran at elevated temperature, for example under reflux.
• a solution of boron trifluoride etherate to 1 mol of the compound of the formula VII and an excess, for example 1.4-3 mol, of sodium cyanoborohydride in tetrahydrofuran at elevated temperature, for example under reflux.
• BF 3 ⁇ O (C 2 H 5 ) 2 in tetrahydrofuran so that the pH of the reaction solution is kept close to the transition point of the bromocresol green indicator, which is also added.
• the reduction with lithium borohydride is preferably carried out in an ether, for example tetrahydrofuran, 1,2-dimethoxyethane or diethylene glycol dimethyl ether, at temperatures between room temperature and reflux temperature.
• a compound of the formula R a- S (O) m H is either a thiol of the formula R a- SH or a sulfinic acid of the formula R a -SO 2 H.
• Suitable salts of the compound of the formula R a ⁇ S (O) m H are, for example, alkali metal salts, for example sodium or potassium salts.
• a compound of the formula R a ⁇ S (O) m H or a suitable salt thereof is added to a compound of the formula VIII in a customary manner in an inert, polar solvent, for example in a polar ether, for example tetrahydrofuran, dioxane or dimethoxyethane, a lower alkanol, for example methanol, ethanol or isopropa nol, or a dipolar aprotic solvent, for example dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide, N-methylpyrrolidone or acetonitrile, optionally also in mixtures of the solvents mentioned with one another or with water, at temperatures between about -30 ° C. and the boiling point of the respective solvent , for example between 0 ° and + 80 ° C, for example around 50 ° C.
• a polar solvent for example in a polar ether, for example tetrahydrofuran,
• the salts thereof are preferably used, for example the sodium or potassium salt.
• a salt of a thiol of the formula R a- SH can also be formed in situ, for example by adding a suitable base, for example alkali metal hydroxide, such as sodium or potassium hydroxide, or alkali metal hydride, for example sodium hydride, although only anhydrous solvents can be used. It is also possible to carry out the addition reaction with a free thiol of the formula R a- SH in the presence of an organic base, for example a tertiary amine, for example triethylamine, N-methylmorpholine, dimethylaniline, diazabicyclo- [5.4.0] undec-7-ene or Diazabicyclo [4.3.0] non-5-enes.
• a suitable base for example alkali metal hydroxide, such as sodium or potassium hydroxide, or alkali metal hydride, for example sodium hydride, although only anhydrous solvents can be used.
• a free thiol of the formula R a- SH in the presence of an
• a compound introducing the R b- (CH Z ) q radical is, for example, the corresponding halide, for example chloride, bromide or iodide, or a reactive ester of the corresponding alcohol, for example a sulfonic acid ester, such as the methanesulfonic acid ester or p-toluenesulfonic acid ester.
• the compound of the formula IX is preferably converted into the corresponding anion using a strong, non-nucleophilic base by the customary methods, for example using the lithium or potassium salt of a sterically hindered secondary amine, for example with lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, lithium or potassium bis (trimethylsilyl) amide or the like.
• Deprotonation with the base is preferably carried out at low temperatures, for example between -100 ° C. and -50 ° C.
• an inert polar solvent for example in a polar ether, for example tetrahydrofuran, dioxane or dimethoxyethane, optionally mixed with a hydrocarbon, for example hexane or Toluene, and / or hexamethylphosphoric triamide or N, N'-dimethyl-N, N'-propyleneurea, carried out.
• a polar ether for example tetrahydrofuran, dioxane or dimethoxyethane
• a hydrocarbon for example hexane or Toluene
• / or hexamethylphosphoric triamide or N, N'-dimethyl-N, N'-propyleneurea carried out.
• the compound of the formula IX contains further, more easily deprotonable methylene or methine groups, for example those in addition to the sulfinyl or sulfonyl group, two or more equivalents of the base are preferably used
• the thus deprotonated compound of the formula IX is preferably in situ at low temperatures, for example at -78 ° to -30 ° C., with the alkylating agent introducing the radical R - (CH 2 ) q - and then warmed to room temperature or slightly elevated temperature, eg at 50 ° C, implemented in the same solvent or solvent mixture.
• the alkylation can be carried out under substantially milder conditions, for example in one of the abovementioned solvents or other polar solvents, for example dimethyl sulfoxide, dimethylformamide or acetonitrile, with which the radical R b (CH Z ) q- Introducing alkylating agent at temperatures between -30 ° C and about room temperature and a tertiary amine, for example triethylamine, N-methylmorpholine, diazabicyclo [5.4.0] undec-7-ene or diazabicyclo [4.3.0] non-5 -en, or an insoluble inorganic base, for example potassium carbonate or sodium hydride, or an alcoholate, for example potassium tert-butoxide.
• solvents or other polar solvents for example dimethyl sulfoxide, dimethylformamide or acetonitrile
• R b (CH Z ) q- Introducing alkylating agent at temperatures between -30 ° C and about room temperature and a tert
• Alkylation under phase transfer conditions ie in a two-phase mixture of aqueous base, for example sodium bicarbonate, is also suitable alkali, and an immiscible organic solvent, for example methylene chloride or toluene, and a phase transfer catalyst, for example an ammonium or phosphonium salt.
• aqueous base for example sodium bicarbonate
• an immiscible organic solvent for example methylene chloride or toluene
• a phase transfer catalyst for example an ammonium or phosphonium salt.
• a carboxamide group can be substituted, a carboxy group present in free or reactive form can be esterified or convert an esterified carboxy group into a carboxy or a carboxamide group.
• Suitable agents for alkylating a carboxamide group in a compound of formula I are e.g. Diazo compounds, e.g. Diazomethane.
• Diazomethane can be decomposed in an inert solvent, the free methylene formed reacting with the carboxamide group in the compound of the formula I.
• the decomposition of diazomethane is preferably catalytic, e.g. in the presence of a noble metal in finely divided form, e.g. Copper, or a precious metal salt, e.g. Copper (I) chloride or copper (II) sulfate.
• alkylating agents are the alkylating agents mentioned in German Offenlegungsschrift 2,331,133, e.g. Alkyl halides, sulfonic acid esters, sea wine salts or 1-substituted 3-aryltriazenes. which can be reacted with a compound of formula I with a carboxamide group under the reaction conditions mentioned there.
• the free acid can be used or the free acid can be converted into one of the reactive derivatives mentioned under process a) and reacted with an alcohol, or the free acid or react a reactive salt, for example the cesium salt, with a reactive derivative of an alcohol.
• a reactive salt for example the cesium salt
• the cesium salt of a carboxylic acid can be reacted with the halide of an alcohol.
• the esterification of a carboxy group can be carried out with the alkylating agents mentioned above for the substitution of the carboxamide group and under the same reaction conditions, e.g. with diazomethane, alkyl halides, sulfonic acid esters, sea wine salts, 1-substituted 3-aryltriazenes etc.
• an esterified carboxy group can be converted into an optionally substituted carboxamide group by aminolysis with ammonia or a primary or secondary amine.
• the aminolysis can be carried out according to the reaction conditions for such reactions mentioned in the Organikum, 15th edition, VEB German Publishing House of Sciences, Berlin (East) 1976.
• the free hydroxyl group for example the hydroxyl group R 4 , can be etherified or esterified.
• the etherification of this hydroxy group can be carried out with the alkylating agents mentioned above and under the same reaction conditions, e.g. with diazomethane, alkyl halides, sulfonic acid esters, sea wine salts, I-substituted 3-aryltriazenes etc.
• the free hydroxy group can be esterified using the customary acylating agents and the customary reaction conditions given in the organic, e.g. with acetic anhydride.
• alkylation reactions, etherifications, esterifications etc. mentioned can also be carried out in a starting material instead of in the end product.
• a thio group can be oxidized to a sulfinyl or sulfonyl group or a sulfinyl group to a sulfonyl group.
• the oxidation to the sulfonyl group can be carried out with most of the usual oxidizing agents.
• Oxidizing agents which selectively use the thio group or sulfinyl group in the presence of other functional groups of the compound of formula I, e.g. the amide function and the hydroxyl group, oxidize, for example aromatic or aliphatic peroxycarboxylic acids, e.g. Perbenzoic acid, monoperphthalic acid, m-chloroperbenzoic acid, peracetic acid, performic acid or trifluoroperacetic acid.
• the oxidation with peroxycarboxylic acids takes place in the customary suitable solvents, for example chlorinated hydrocarbons, e.g.
• Methylene chloride or chloroform, ether, ethyl acetate or the like at temperatures between -78 ° C and room temperature, e.g. between -20 ° C and + 10 ° C, preferably around 0 ° C.
• the peroxycarboxylic acid can also be formed in situ, e.g. with hydrogen peroxide in acetic acid or formic acid, optionally containing acetic anhydride, e.g. with 30% or 90% hydrogen peroxide in acetic acid / acetic anhydride.
• Other peroxo compounds are also suitable, for example potassium peroxomonosulfate in lower alkanol / water mixtures, e.g.
• Methanol water or ethanol water, or in aqueous acetic acid Temperatures between -70 ° C and + 30 ° C, e.g. between -20 ° C and room temperature, also sodium metaperiodate in methanol or methanol-water mixtures at temperatures between 0 ° C and 50 ° C, e.g. around room temperature.
• selective oxidizing agents are used in equimolar amounts or only a slight excess under controlled reaction conditions in order to avoid overoxidation to the sulfonyl group.
• sodium metaperiodate in methanol or methanol-water mixtures at temperatures between -15 ° C and room temperature e.g.
• this group can be reduced to a thio group.
• Selective reducing agents which contain other functional groups of the compound of formula I, e.g. the amide function, leave unchanged.
• Examples of such selective reducing agents are dichloroborane, which is preferably used in tetrahydrofuran or dimethoxyethane at temperatures between -30 ° C and + 10 ° C, triphenylphosphine in boiling carbon tetrachloride, trichlorosilane or hexachlorodisilane, iron pentacarbonyl, furthermore sodium hydrogen sulfite in solvents, e.g.
• a sulfonyl group can be reduced to a thio group in an available compound of the formula I, for example with diisobutylaluminum hydride in ether or tetrahydrofuran.
• a sulfenamide group can be oxidized to the sulfonamide with one of the reagents mentioned under the oxidation of thio group to sulfonyl group, for example potassium peroxomonosulfate, and hydrolyzed immediately in situ.
• a sulfonic acid ester group can also be converted into a sulfo group by acid or base, for example as described above for the hydrolysis of a carboxylic acid ester group.
• this can be converted into a sulfonic acid ester or sulfonamide group in a known manner, for example by conversion into a sulfonic acid halide group and reaction with an alcohol, phenol or amine.
• a sulfonic acid ester group is converted into the corresponding sulfonamide group analogously to the carboxylic acid ester group with an amine.
• these groups e.g. Carboxy, amino, hydroxy, mercapto and / or sulfo groups, in a manner known per se, by means of solvolysis, in particular hydrolysis, if appropriate enzymatic hydrolysis, alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis, or chemical reduction, if appropriate stepwise or released at the same time.
• solvolysis in particular hydrolysis, if appropriate enzymatic hydrolysis, alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis, or chemical reduction, if appropriate stepwise or released at the same time.
• protected carboxy for example tert-lower alkoxycarbonyl, in the 2-position by an organic silyl group or in the 1-position by lower alkoxy or lower alkylthio substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl, by treatment with a suitable acid, for example formic acid or trifluoroacetic acid, optionally with addition convert a nucleophilic compound, eg phenol or anisole, into free carboxy.
• a suitable acid for example formic acid or trifluoroacetic acid
• a nucleophilic compound eg phenol or anisole
• optionally substituted benzyloxycarbonyl can, for example, by means of hydrogenolysis, ie by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as one Palladium catalyst are released.
• a metallic hydrogenation catalyst such as one Palladium catalyst
• suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl
• an alkali metal dithionite for example sodium dithionite
• 2-halogeno lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted into free carboxy.
• Aroylmethoxycarbonyl can also be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent such as sodium thiophenolate or sodium iodide.
• 2-tri-lower alkylsilyl-lower alkoxycarbonyl can also be obtained by treatment with a hydrofluoric acid salt which provides the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, optionally in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as Tetraniederalkylammoniumfluorid or tri-lower alkylarylammonium fluoride, such as tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent such as dimethyl sulfoxide or N, N-dimethylacetamide, are converted into free carboxy.
• a hydrofluoric acid salt which provides the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride
• a macrocyclic polyether such as
• Carboxy esterified with an organic silyl group such as tri-lower alkylsilyl, for example trimethylsilyl
• an organic silyl group such as tri-lower alkylsilyl, for example trimethylsilyl
• Esterified carboxy can also be cleaved enzymatically, for example esterified arginine or lysine, such as lysine methyl ester, using trypsin.
• a protected amino group is released in a manner known per se and in various ways depending on the nature of the protective groups, preferably by means of solvolysis or reduction.
• 2-halo-lower alkoxycarbonylamino (optionally after converting a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be, for example, treated with a suitable reducing agent, such as zinc, in the presence of a suitable carboxylic acid, such as aqueous acetic acid.
• Aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, for example sodium, dithionite.
• a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate
• 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, for example sodium, dithionite.
• Optionally substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-tri-lower alkylsilyl-lower alkoxycarbonylamino can be obtained by treatment with a suitable acid, for example formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino, for example by means of hydrogenolysis, ie by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, optionally substituted catalyst Triarylmethylamino or formylamino, for example by treatment with an acid, such as mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, optionally in the presence of water, and an amino group protected with an organic silyl group, for example by means of hydrolysis or alcoholysis will.
• a suitable acid for example formic or trifluoroacetic acid
• benzyloxycarbonylamino for example by means of hydrogeno
• An amino group protected by 2-haloacetyl for example 2-chloroacetyl
• 2-chloroacetyl can be released by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate of thiourea, and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting substitution product.
• An amino group protected by 2-tri-lower alkylsilyl-lower alkoxycarbonyl can also be treated with a fluoride anion salt of the hydrogen fluoride acid, as indicated above in connection with the release of an appropriately protected carboxy group, can be converted into the free amino group. It is also possible to split off silyl, such as trimethylsilyl, bonded directly to a heteroatom, such as nitrogen, by means of fluoride ions.
• Amino protected in the form of an azido group is e.g. converted into free amino by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or also by treatment with zinc in the presence of an acid such as acetic acid.
• the catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, e.g. Methylene chloride, or in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at about 20 ° C to 30 ° C, or with cooling or heating.
• a hydroxyl or mercapto group protected by a suitable acyl group, an organic silyl group or by optionally substituted 1-phenyl-lower alkyl is released analogously to a correspondingly protected amino group.
• a hydroxy or mercapto group protected by 2,2-dichloroacetyl is e.g. by basic hydrolysis, a group protected by tert-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical by acidolysis, e.g. by treatment with a mineral acid or a strong carboxylic acid, e.g. Trifluoroacetic acid, released.
• a silyl group e.g.
• a trimethylsilyl or tert-butyldimethylsilyl group is also removed by acidolysis, e.g. split off by mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid.
• 2-halo lower alkoxycarbonyl is replaced by the above reducing agents, e.g. reducing metal, such as zinc, reducing metal salts, such as chromium II salts, or by sulfur compounds, for example sodium dithionite or preferably sodium sulfide and carbon disulfide.
• Two hydroxy groups which are linked together by means of a preferably substituted methylene group such as by lower alkylidene, e.g. Isopropylidene, cycloalkylidene, e.g. Cyclohexylidene, or benzylidene, can be protected by acid hydrolysis, e.g. in the presence of a mineral acid or a strong organic acid.
• a preferably substituted methylene group such as by lower alkylidene, e.g. Isopropylidene, cycloalkylidene, e.g. Cyclohexylidene, or benzylidene
• a sulfo group protected as a sulfonic acid ester or sulfonamide is removed, for example, by acid hydrolysis, e.g. in the presence of mineral acid, or preferably by basic hydrolysis, e.g. released with alkali metal hydroxide or alkali metal carbonate, for example sodium carbonate.
• Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se. So one can salts of compounds of formula 1 with acidic groups e.g. by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, or with inorganic alkali or alkaline earth metal salts, e.g. Form sodium bicarbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.
• Acid addition salts of compounds of formula I are obtained in a conventional manner, e.g. by treatment with an acid or a suitable anion exchange reagent.
• Salts can be converted into the free compounds in a conventional manner: metal and ammonium salts e.g. by treatment with suitable acids, acid addition salts e.g. by treating with a suitable basic agent.
• Mixtures of stereoisomers, especially mixtures of diastereomers, can be prepared in a manner known per se, e.g. fractionated into individual isomers by fractional crystallization, chromatography, etc.
• Racemates can be used in a manner known per se, e.g. after the optical antipodes have been converted into diastereomers, for example by reaction with optically active acids or bases.
• the configuration can be reversed in a targeted manner at individual chirality centers in a compound of the formula I, for example the CH-R 4 -C atom.
• the configuration on the CH-R 4 -C atom can be reversed by second-order nucleophilic substitution according to method d) after conversion of the group R 4 into a nucleofugic leaving group X and reaction with a reagent introducing the same substituent R 4 .
• the invention also relates to those embodiments of the process in which one starts from a compound which is obtainable as an intermediate at any stage and carries out the missing steps or the process is terminated at any stage or a compound which is obtainable by the process according to the invention is produced under the process conditions and in further processed in situ.
• the pharmacologically useful compounds of the present invention can e.g. be used for the production of pharmaceutical preparations which contain an effective amount of the active ingredient together or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically usable excipients.
• the pharmaceutical preparations according to the invention are those for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals), which contain an effective dose of the pharmacological active ingredient alone or together with a significant Contain an amount of a pharmaceutically usable carrier material.
• enteral such as nasal, rectal or oral
• parenteral such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals)
• the dosage of the active ingredient depends on the warm-blooded species, body weight, age and individual condition, the disease to be treated and the mode of administration.
• the warm-blooded animals e.g. People of about 70 kg body weight, dosage amounts to be administered are between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, e.g. at about 300 mg per person per day, preferably in 1 to 3 single doses, e.g. can be the same size. Children are usually given half the dose of adults.
• the new pharmaceutical preparations contain from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient.
• Pharmaceutical preparations according to the invention can e.g. in unit dose form, such as ampoules, vials, suppositories, dragees, tablets or capsules.
• the pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g. by means of conventional solution, lyophilization, mixing, granulating or coating processes.
• Solutions of the active ingredient are preferably used, as well as suspensions, in particular isotonic aqueous solutions or suspensions, these being able to be prepared before use, for example in the case of lyophilized preparations which contain the active substance alone or together with a carrier material, for example mannitol.
• the pharmaceutical preparations can be sterilized and / or auxiliary substances, for example preservatives, stabilizers, wetting agents and / or Contain emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers and are produced in a manner known per se, for example by means of conventional solution or lyophilization processes.
• the solutions or suspensions mentioned can contain viscosity-increasing substances, such as sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone or gelatin.
• Suspensions in oil contain as an oily component the vegetable, synthetic or semi-synthetic oils commonly used for injection purposes.
• liquid fatty acid esters are to be mentioned in particular, as the acid component a long-chain fatty acid with 8-22, especially 12-22, carbon atoms, such as lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachic acid, behenic acid or corresponding unsaturated acids such as oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid.
• the alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a mono- or polyhydric, for example mono-, di- or trihydric alcohol, for example methanol, ethanol, propanol, butanol or pentanol or their isomers, but especially glycol or glycerin.
• fatty acid esters ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2735” (polyoxyethylene glycerol trioleate from Gattefosse, Paris), "Myglyol 812” (triglyceride of saturated fatty acids with chain length G ⁇ to C 12 from Chemische Werke Witten / Ruhr, Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and especially peanut oil.
• injection preparations are manufactured in the usual way under sterile conditions, as are the filling in ampoules or vials and the closure of the containers.
• compositions for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained and the mixture or granules, if desired or necessary after the addition of suitable auxiliaries, processed into tablets or dragee cores. They can also be installed in plastic carriers that release the active ingredients in doses or allow them to diffuse.
• Suitable carriers are in particular fillers such as sugar, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch paste using e.g.
• Dragee cores are provided with suitable, possibly enteric coatings, whereby one of the things Concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. Colorants or pigments, e.g. for identification or for labeling different doses of active ingredient.
• New starting materials and / or intermediates and processes for their preparation are also the subject of the present invention. Such starting materials are preferably used and the reaction conditions are selected so that the compounds listed as preferred are obtained.
• the starting materials for carrying out process a) can be prepared by processes known per se, for example from the amino acids in question by condensation analogously to process a) described above. For example, one can use a compound of the formula similar to the process described in European patent application EP 143 746.
• Suitable functional derivatives of a carboxylic acid of formula XI are, for example, the corresponding lithium salt of the carboxylic acid, a carboxylic acid halide, e.g. Carboxylic acid chloride, an anhydride, e.g. the symmetrical carboxylic acid anhydride or a mixed carboxylic acid anhydride with a sterically hindered carboxylic acid, e.g. with pivalic acid, or a thioester, e.g. 2-pyridylthioester.
• a carboxylic acid halide e.g. Carboxylic acid chloride
• an anhydride e.g. the symmetrical carboxylic acid anhydride or a mixed carboxylic acid anhydride with a sterically hindered carboxylic acid, e.g. with pivalic acid
• a thioester e.g. 2-pyridylthioester.
• reaction of a carboxylic acid of formula XI or a suitable functional derivative thereof with a compound of formula IV is carried out in the usual manner, e.g. according to the reaction conditions given in process c), but optionally with cooling, e.g. at temperatures from approx. -50 ° C to approx. 0 ° C.
• a 2-pyridylthioester of the carboxylic acid of the formula XI is reacted with a bromine magnesium compound of the formula IV.
• Compounds of the formula III can be prepared by processes known per se, for example by converting the carboxy group in a compound of the formula XI in which the substituents have the meanings mentioned and free functional groups are optionally in protected form, for example by methods known per se the corresponding methyl or ethyl ester, via an imidazolide or an N-methoxy-N-methylamide, is reduced to the aldehyde function.
• Compounds of the formula IV can be obtained, for example, by reacting a halide of the formula known or which can be prepared by methods known per se for example the chloride, with a metalating agent, for example magnesium, lithium or tert-butyllithium.
• a metalating agent for example magnesium, lithium or tert-butyllithium.
• Nitriles of formula VI are prepared, for example, by using a compound of formula wherein the substituents have the meanings mentioned, with a salt of hydrocyanic acid.
• Suitable salts of hydrocyanic acid should be sufficiently soluble in the chosen inert solvent so that a reaction can take place.
• Such salts are e.g. Ammonium cyanide, alkali metal or alkaline earth metal cyanides, e.g. Sodium or potassium cyanide, or transition metal cyanides, e.g. Copper cyanide. The latter are suitable because of their lower basicity compared to the alkali metal cyanides.
• the nitrile form is preferably formed when e.g. the reaction takes place with metal cyanides whose metal cations have a lower atomic weight than that of copper.
• Suitable inert solvents are, above all, polar, aprotic solvents, for example carboxamides, e.g. Dimethylformamide or dimethylacetamide, nitriles, e.g. Acetonitrile or propionitrile, or di-lower alkyl sulfoxides, e.g. Dimethyl sulfoxide.
• carboxamides e.g. Dimethylformamide or dimethylacetamide
• nitriles e.g. Acetonitrile or propionitrile
• di-lower alkyl sulfoxides e.g. Dimethyl sulfoxide.
• the reaction takes place at room temperature, at reduced or at elevated temperature, e.g. in a temperature range from about -40 ° C to about + 100 ° C, preferably from about -10 ° C to about + 50 ° C and, if desired, in an inert gas, e.g. Nitrogen atmosphere.
• an inert gas e.g. Nitrogen atmosphere.
• Epoxides of the formula VII are prepared, for example, by using a compound of the formula wherein Z 1 is an amino protecting group, with a phosphoranylidene compound of the formula wherein R c represents an optionally substituted hydrocarbon radical, R 5 has the meaning given and Z z is a carboxy protecting group, and an available compound of the formula converted into an epoxide with an oxidizing agent containing the peroxy group and, in an available compound, splitting off the protective groups Z 1 and Z 2 in any order of the reaction steps and replacing them with the groups Ri-A- and R 6 .
• R c is preferably phenyl.
• the reaction of a compound of formula XIV with a phosphoranylidene compound of formula XV takes place under the reaction conditions known for Wittig reactions and described, for example, in the organic.
• the resulting olefin of the formula XVI is optionally reacted in situ with the oxidizing agent, for example peracetic acid or m-chloroperbenzoic acid.
• the oxidizing agent for example peracetic acid or m-chloroperbenzoic acid.
• Compounds of formula VIII are prepared, for example, by using an acrylic acid of the formula or a suitable functional derivative thereof with a compound of the formula implemented according to method a).
• the compound of the formula XVIII is likewise prepared according to process a) from an amino acid of the formula HA-OH protected on the amino group and a compound of the formula X and subsequent cleavage of the protective group, if appropriate before or after introduction of the radicals R 2 and R 4 .
• R f (A) means that the R f value was determined in system A.
• the quantitative ratio of the solvents to one another is given in parts by volume.
• the fragment called -Cha c -Val- means the divalent radical of (2S, 4S, 5S) -5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid and has the formula
• the fragment with the designation -Cha cx Val- is derived from the fragment -Cha-Val- by bridging NH and OH with an isopropylidene group and has the formula
• Gly (R 3 ) c Gly (R 5 ) means the divalent radical of 2-R 5 -4 (S) -hydroxy-5-amino-5-R 3 -pentanoic acid with (R) - or ( S) configuration at C atom 2 or 5 and has the formula
• the fragment called -Gly (R 3 ) cx Gly (R 5 ) - is derived from the fragment -Gly (R 3 ) c Gly (R 5 ) - by bridging NH and OH with an isopropylidene group.
• the fragment labeled - (S) -Gly (R 3 ) c Val- therefore means the divalent radical of 2 (S) -isopropyl-4 (S) -hydroxy-5 (S) -amino-5-R3-pentanoic acid .
• the starting material is produced as follows: a) 2-Benzyl-3-tert-butylthio-propionic acid: 0.5 g of 2-benzyl-3-tert-butylthio-propionic acid ethyl ester are dissolved in 5 ml of THF and with 3.2 ml of water and 0.9 ml of 2 N Potassium hydroxide solution added. The mixture is stirred at room temperature overnight, neutralized with 0.9 ml of 2N hydrochloric acid and evaporated. The residue is purified by flash chromatography on 30 g of silica gel 60 (mobile phase H). Yellow O el, 1 H-NMR (DMSO-d 6): 1.23 ppm (s, 9H); 2.55-2.9 (m, 5H); 7.15-7.3 (m, 5H); 12.4 (s, 1H).
• Example 2 Analogously to Example 2, the title compound is prepared starting from 50 mg H-His-Cha c Val-n-butylamide, 34 mg 2 (S) -benzyl-3-tert-butylsulfonyl-propionic acid, 18 mg HOBt and 29 mg DCCI and by flash Chromatography on 30 g of silica gel 60 (eluent M) purified.
• R f (N) 0.09;
• R f (Y) 0.57;
• R f (O) 0.35.
• the starting material is produced as follows:
• the pure title compound can also be obtained by fractional crystallization of the (+) - dehydroabietylammonime salts of racemic acid in isopropanol and cleavage of the diastereomerically pure crystals.
• the starting material is produced as follows:
• the starting material 2-benzyl-3-isopropylsulfonyl-propionic acid is prepared analogously to Example 1 m), n) and o) from ethyl a-benzyl acrylic acid and isopropyl mercaptan.
• the starting material 3-ethylsulfonyl-2-benzyl-propionic acid is prepared analogously to Example lm), n) and o) from ethyl a-benzyl acrylic acid and ethyl mercaptan.
• the starting material 2-benzyl-3-diethylaminosulfonyl-propionic acid is prepared analogously to Example 14a) and b).
• the starting material 2-benzyl-3-isopropylaminosulfonyl-propionic acid is prepared analogously to Example 14a) and b).
• Example 20 N- (2 (R, S) -benzyl-3-tert-but y lsulfonyl-propionyl) -His-Cha Val - ((S) -5-amino-5-carboxv-pentyl) amide
• the starting material 2-benzyl-3- [1-methyl-2-imidazolylthio] propionic acid is prepared analogously to Example 29a) and lm) from ethyl a-benzylacrylic acid and 2-mercapto-l-methyl-imidazole.
• the starting material 2-benzyl-3-phenylsulfonyl-propionic acid is prepared analogously to Example lm), n) and o) from ethyl a-benzyl acrylic acid and thiophenol.
• the starting material 2-benzyl-3-pyrrolidinosulfonyl-propionic acid is prepared analogously to Example 14a) and b).
• the starting material 3-ethylthio-2-benzyl-propionic acid is prepared analogously to Example 4a) and lm) from ethyl a-benzylacrylate and ethyl mercaptan.
• Example 39 5 (S) - [N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -histidinyl] -amino-6-cyclohexyl-4 (R) - and 4 (S) -hydroxy- 2 (S) -isopropyl-hexanoic acid-n-butylamide
• Example 40 N- (2 (S) -benzyl-3-tert-butvlsulfon y l-propionyl) -His-Cha c Val-n-butylamide by an alternative condensation reaction
• the initial material is produced as follows:
• Example 41 N- (2 (R, S) -benzyl-3-tert-but y y lsulfon l-propionyl) -His-Cha c Val-n-butylamide by oxidation of the sulfinyl compound
• Example 43 N- (2 (R, S) -benzyl-3-tert-but y lsulfonyl-propionyl) -His-Cha c Val-n-butylamide by cleavage of a silyl protecting group
• Example 44 N- (2 (R, S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha c Val-n-butylamide by splitting off the 2-chloroethoxycarbonyl protective group
• the starting material is prepared analogously to Example 43a) and b) from Z-Cha c val-n-butylamide and 2-chloroethoxychloroformate and condensation with histidine and 2-benzyl-3-tert-butylsulfonyl-propionic acid.
• Example 45 Alternative reaction conditions for the preparation of N- (2 (R, S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha c Val-n-butylamide by condensation
• a sterile-filtered aqueous solution of N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha c Val-n-butylamide is heated under aseptic conditions with a sterile gelatin solution containing phenol as a preservative mixed so that 1.0 ml solution has the following composition:
• the mixture is filled into vials of 1.0 ml under aseptic conditions.
• Example 48 Sterile dry substance for injection
• a mixture of the N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha c Val-n-butylamide, 50 g of corn starch and the colloidal silica is made with starch paste from 250 g of corn starch and 2.2 kg of demineralized water processed into a moist mass. This is passed through a sieve of 3 mm mesh size and dried at 45 ° for 30 minutes in a fluidized bed dryer.
• the dry granulate is pressed through a sieve with a mesh size of 1 mm, mixed with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and compressed to give tablets which are slightly curved.
• the compacts are coated in a coating pan of 45 cm in diameter with a solution of 20 g of shellac and 40 g of hydroxypropylmethylcellulose (low viscosity) in 110 g of methanol and 1350 g of methylene chloride by uniform spraying for 30 minutes. it is dried by simultaneously blowing in air at 60 °.

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• 1987
  • 1987-02-04 EP EP87101502A patent/EP0236734A3/fr not_active Withdrawn
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• 1989
  • 1989-04-19 US US07/341,239 patent/US4889869A/en not_active Expired - Fee Related
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